Ladostigil Therapy For Immunomodulation

Abstract

Methods for treating individuals suffering from inflammation, specifically systemic inflammation including septic shock and inflammatory conditions affecting the gastrointestinal, myocardial and endocrine systems with ladostigil.

Description

FIELD OF THE INVENTION

[0001] The invention relates to pharmaceutical compositions and dosage units comprising ladostigil and methods of using the same for inhibiting inflammation.BACKGROUND OF THE INVENTION

[0002] Inflammation is a biological response to injury, infection or irritation in which a cascade of cellular and microvascular reactions serves to eradicate the infection, remove damaged tissue and generate new tissue. Immune responses mediated by various immune effectors and mediators initiate and tightly regulate the inflammatory response. However, while the normal immune system is closely regulated, aberrations in immune responses are not uncommon. Such dysregulated or excessive inflammatory reactions may result in potentially harmful processes, leading in turn to organ damage and various pathologies due to excessive exposure to inflammatory mediators or cellular effectors. These include acute pathologies such as septic shock, and chronic pathologies such as chronic gastrointes...

Examples

example 1

Experimental Colitis and Gastrointestinal Inflammation

Acute Colitis Induced by DSS in Mice

[0191]BALB / c OlaHsd male mice aged 8-9 weeks and weighing 25-30 g were purchased from Harlan (Jerusalem, Israel) and housed in standard cages of up to 5 per cage in the pathogen free Animal Facility of the Institute for Drug Research. All experiments were performed in accordance with the Principles of Laboratory Animal Care (NIH publication #85-23, revised 1985) protocols MD-09-12197-4. Acute colitis was induced in mice by administration of 5% DSS solution (M.Wt.=36,000−50, MP Biomedicals, LLC, Solon, Ohio, USA) in water for 8 days. The DSS solution was freshly prepared every day. Mice were provided with food and water or DSS solution ad libitum during the experiment. They were divided into groups of 10 as follows: Vehicle control group: mice drank water and were given water (1 ml / 100 gm) once daily by gavage for 8 days; Drug control group: mice drank water and were given ladostigil (10 mg / kg) ...

example 2

Myocardial Ischemic Preconditioning

Methods

[0206]Four groups of male rats of the Wistar strain were used for these studies; a) 3-months old untreated; b) 22 months old, untreated; c) 22 months old treated from the age of 16 months by daily oral administration of ladostigil hemitartrate at a dose of 1 mg / kg / day (hereinafter “low dose”; d) 22 months old treated from the age of 16 months by daily oral administration of ladostigil hemitartrate at a dose of 8.5 mg / kg / day (hereinafter “high dose”). Only the latter dose was shown to inhibit MAO-A after chronic treatment in rats.

[0207]On the day of the experiment, rats were injected with i.p. sodium heparin (500 units / kg) followed 30 min later by 80 mg / kg ketamine plus 5 mg / kg xylazine i.p. Bilateral thoracotomy was performed and hearts with a segment of the ascending aorta were rapidly excised, put in ice-cold heparinized saline and mounted onto the Langendorff apparatus. They were perfused with a modified Krebs-Henseleit (KH) buffer as des...

example 3

Diabetes

[0212]Male Psammomys obesus gerbils aged 3.5-4 months were given a high-energy diet consisting of 938.5 g / Kg version of 2018SC+F Harlan Tekled Ltd., USA, supplemented with soybean oil to a final fat concentration of 6%. After one week on the diet, blood was taken for measurement of glucose and ChE activity. Half of the animals were given ladostigil (17 mg / kg / day) by gavage while the remainder received tap water by the same route. Blood was taken from the tail once weekly for measurement of glucose as described in Kalman R., et al, (2001). Lab Anim. 35:346-352. After three weeks of treatment the animals they were deeply anesthetized, blood was taken by cardiac puncture for measurement of ChE activity, glucose and insulin levels and the pancreas removed for section and staining with haematoxylin and eosin and the number of islets counted. Initial and final glucose and insulin levels are shown in the Table 3. Blood glucose of 11 animals had reached values exceeding 200 mg / dL af...

FIELD OF THE INVENTION

[0001] The invention relates to pharmaceutical compositions and dosage units comprising ladostigil and methods of using the same for inhibiting inflammation.BACKGROUND OF THE INVENTION

[0002] Inflammation is a biological response to injury, infection or irritation in which a cascade of cellular and microvascular reactions serves to eradicate the infection, remove damaged tissue and generate new tissue. Immune responses mediated by various immune effectors and mediators initiate and tightly regulate the inflammatory response. However, while the normal immune system is closely regulated, aberrations in immune responses are not uncommon. Such dysregulated or excessive inflammatory reactions may result in potentially harmful processes, leading in turn to organ damage and various pathologies due to excessive exposure to inflammatory mediators or cellular effectors. These include acute pathologies such as septic shock, and chronic pathologies such as chronic gastrointes...

Examples

example 1

Experimental Colitis and Gastrointestinal Inflammation

Acute Colitis Induced by DSS in Mice

[0191]BALB / c OlaHsd male mice aged 8-9 weeks and weighing 25-30 g were purchased from Harlan (Jerusalem, Israel) and housed in standard cages of up to 5 per cage in the pathogen free Animal Facility of the Institute for Drug Research. All experiments were performed in accordance with the Principles of Laboratory Animal Care (NIH publication #85-23, revised 1985) protocols MD-09-12197-4. Acute colitis was induced in mice by administration of 5% DSS solution (M.Wt.=36,000−50, MP Biomedicals, LLC, Solon, Ohio, USA) in water for 8 days. The DSS solution was freshly prepared every day. Mice were provided with food and water or DSS solution ad libitum during the experiment. They were divided into groups of 10 as follows: Vehicle control group: mice drank water and were given water (1 ml / 100 gm) once daily by gavage for 8 days; Drug control group: mice drank water and were given ladostigil (10 mg / kg) ...

example 2

Myocardial Ischemic Preconditioning

Methods

[0206]Four groups of male rats of the Wistar strain were used for these studies; a) 3-months old untreated; b) 22 months old, untreated; c) 22 months old treated from the age of 16 months by daily oral administration of ladostigil hemitartrate at a dose of 1 mg / kg / day (hereinafter “low dose”; d) 22 months old treated from the age of 16 months by daily oral administration of ladostigil hemitartrate at a dose of 8.5 mg / kg / day (hereinafter “high dose”). Only the latter dose was shown to inhibit MAO-A after chronic treatment in rats.

[0207]On the day of the experiment, rats were injected with i.p. sodium heparin (500 units / kg) followed 30 min later by 80 mg / kg ketamine plus 5 mg / kg xylazine i.p. Bilateral thoracotomy was performed and hearts with a segment of the ascending aorta were rapidly excised, put in ice-cold heparinized saline and mounted onto the Langendorff apparatus. They were perfused with a modified Krebs-Henseleit (KH) buffer as des...

example 3

Diabetes

[0212]Male Psammomys obesus gerbils aged 3.5-4 months were given a high-energy diet consisting of 938.5 g / Kg version of 2018SC+F Harlan Tekled Ltd., USA, supplemented with soybean oil to a final fat concentration of 6%. After one week on the diet, blood was taken for measurement of glucose and ChE activity. Half of the animals were given ladostigil (17 mg / kg / day) by gavage while the remainder received tap water by the same route. Blood was taken from the tail once weekly for measurement of glucose as described in Kalman R., et al, (2001). Lab Anim. 35:346-352. After three weeks of treatment the animals they were deeply anesthetized, blood was taken by cardiac puncture for measurement of ChE activity, glucose and insulin levels and the pancreas removed for section and staining with haematoxylin and eosin and the number of islets counted. Initial and final glucose and insulin levels are shown in the Table 3. Blood glucose of 11 animals had reached values exceeding 200 mg / dL af...

Images